American Thoracic Society Documents An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (FE NO ) for Clinical Applications Raed A. Dweik, Peter B. Boggs, Serpil C. Erzurum, Charles G. Irvin, Margaret W. Leigh, Jon O. Lundberg, Anna-Carin Olin, Alan L. Plummer, D. Robin Taylor, on behalf of the American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels (FE NO ) for Clinical Applications THIS OFFICIAL CLINICAL PRACTICE GUIDELINE OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS,MAY 2011 CONTENTS Executive Summary Introduction Methods Committee Composition, Meetings, and Document Preparation Document Structure Quality of Evidence and Strength of Recommendations Why Should a FE NO Test be Obtained? Can FE NO Be Used to Diagnose Asthma? FE NO Is Associated with Eosinophilic Airway Inflammation FE NO Predicts Likelihood of Corticosteroid Responsiveness FE NO Can Support a Diagnosis of Asthma FE NO May Predict AHR Is There a Normal FE NO Value? Normal Values versus Relevant Cut Points for FE NO Confounding Factors that May Affect FE NO What Are the Clinically Significant Cut Points for FE NO ? Low FE NO (, 25 ppb in Adults; 20 ppb in Children) High FE NO (. 50 ppb in Adults, 35 ppb in Children) Intermediate FE NO (between 25 ppb and 50 ppb in Adults; 20–35 ppb in Children) Persistently High FE NO (. 50 ppb in adults, 35 ppb in Children) Can FE NO Be Used to Monitor Airway Inflammation? Monitoring Airway Inflammation in Asthma Minimally Important Differences, and Prognostic Significance of FE NO How Should a FE NO Measurement Be Interpreted and Reported? Other Situations in which FE NO May Be Useful COPD Pulmonary Hypertension Cystic Fibrosis and Nasal NO Measurements Conclusions and Future Directions Online Supplement Appendix E1: Methods Checklist Appendix E2: Technical Considerations and Sources of Variation in FE NO Appendix E3: Causes of High and Low FE NO Levels Appendix E4: Case Studies Background: Measurement of fractional nitric oxide (NO) concentra- tion in exhaled breath (FE NO ) is a quantitative, noninvasive, simple, and safe method of measuring airway inflammation that provides a complementary tool to other ways of assessing airways disease, including asthma. While FE NO measurement has been standardized, there is currently no reference guideline for practicing health care providers to guide them in the appropriate use and interpretation of FE NO in clinical practice. Purpose: To develop evidence-based guidelines for the interpreta- tion of FE NO measurements that incorporate evidence that has accu- mulated over the past decade. Methods: We created a multidisciplinary committee with expertise in the clinical care, clinical science, or basic science of airway disease and/or NO. The committee identified important clinical questions, synthesized the evidence, and formulated recommendations. Rec- ommendations were developed using pragmatic systematic reviews of the literature and the GRADE approach. Results: The evidence related to the use of FE NO measurements is reviewed and clinical practice recommendations are provided. Conclusions: In the setting of chronic inflammatory airway disease including asthma, conventional tests such as FEV 1 reversibility or provocation tests are only indirectly associated with airway inflam- mation. FE NO offers added advantages for patient care including, but not limited to (1) detecting of eosinophilic airway inflammation, (2) determining the likelihood of corticosteroid responsiveness, (3) monitoring of airway inflammation to determine the potential need for corticosteroid, and (4) unmasking of otherwise unsuspected non- adherence to corticosteroid therapy. Keywords: nitric oxide; asthma; inflammation; airway disease; exhaled breath; clinical application EXECUTIVE SUMMARY Nitric oxide (NO) is now recognized as a biological mediator in animals and humans. NO is produced by the human lung and is present in the exhaled breath. It has been implicated in the path- ophysiology of lung diseases, including asthma. The measure- ment of exhaled NO has been standardized for clinical use. Numerous studies have provided evidence regarding the appli- cations of NO measurements in clinical practice, together with the performance characteristics and the strengths and the weak- nesses of the test. Based on this evidence, this Clinical Practice Guideline is designed to guide clinicians as to how exhaled NO measurements should be used and interpreted. EVIDENCE QUALITY AND RECOMMENDATIONS These recommendations may vary with respect to the particular target population. Where this is the case, this has been included This article has an online supplement, which is available from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 184. pp 602–615, 2011 DOI: 10.1164/rccm.912011ST Internet address: www.atsjournals.org
14
Embed
Interpretation of Exhaled Nitric Oxide Levels - American Thoracic
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
American Thoracic Society Documents
An Official ATS Clinical Practice Guideline:Interpretation of Exhaled Nitric Oxide Levels (FENO)for Clinical Applications
Raed A. Dweik, Peter B. Boggs, Serpil C. Erzurum, Charles G. Irvin, Margaret W. Leigh, Jon O. Lundberg,Anna-Carin Olin, Alan L. Plummer, D. Robin Taylor, on behalf of the American Thoracic Society Committeeon Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications
THIS OFFICIAL CLINICAL PRACTICE GUIDELINE OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF
DIRECTORS, MAY 2011
CONTENTS
Executive SummaryIntroductionMethods
CommitteeComposition,Meetings, andDocument PreparationDocument StructureQuality of Evidence and Strength of Recommendations
Why Should a FENO Test be Obtained?Can FENO Be Used to Diagnose Asthma?
FENO Is Associated with Eosinophilic Airway InflammationFENO Predicts Likelihood of Corticosteroid ResponsivenessFENO Can Support a Diagnosis of AsthmaFENO May Predict AHR
Is There a Normal FENO Value?Normal Values versus Relevant Cut Points for FENO
Confounding Factors that May Affect FENO
What Are the Clinically Significant Cut Points for FENO?Low FENO (, 25 ppb in Adults; 20 ppb in Children)High FENO (. 50 ppb in Adults, 35 ppb in Children)Intermediate FENO (between 25 ppb and 50 ppb in Adults;
20–35 ppb in Children)Persistently High FENO (. 50 ppb in adults, 35 ppb in Children)
Can FENO Be Used to Monitor Airway Inflammation?Monitoring Airway Inflammation in AsthmaMinimally Important Differences, and Prognostic Significance
of FENO
How Should a FENO Measurement Be Interpreted and Reported?Other Situations in which FENO May Be Useful
COPDPulmonary HypertensionCystic Fibrosis and Nasal NO Measurements
Conclusions and Future DirectionsOnline Supplement
Appendix E1: Methods ChecklistAppendix E2: Technical Considerations and Sources ofVariation
in FENO
Appendix E3: Causes of High and Low FENO LevelsAppendix E4: Case Studies
Background: Measurement of fractional nitric oxide (NO) concentra-tion in exhaled breath (FENO) is a quantitative, noninvasive, simple,and safe method of measuring airway inflammation that providesa complementary tool to other ways of assessing airways disease,including asthma.While FENO measurement has been standardized,there is currently no reference guideline for practicing health careproviders to guide them in the appropriate use and interpretation ofFENO in clinical practice.Purpose: To develop evidence-based guidelines for the interpreta-tion of FENOmeasurements that incorporate evidence that has accu-mulated over the past decade.Methods:We created amultidisciplinary committeewith expertise inthe clinical care, clinical science, or basic science of airway diseaseand/or NO. The committee identified important clinical questions,synthesized the evidence, and formulated recommendations. Rec-ommendationswere developed using pragmatic systematic reviewsof the literature and the GRADE approach.Results: The evidence related to the use of FENO measurements isreviewed and clinical practice recommendations are provided.Conclusions: In the setting of chronic inflammatory airway diseaseincluding asthma, conventional tests such as FEV1 reversibility orprovocation tests are only indirectly associated with airway inflam-mation. FENOoffers addedadvantages for patient care including,butnot limited to (1) detecting of eosinophilic airway inflammation, (2)determining the likelihood of corticosteroid responsiveness, (3)monitoring of airway inflammation to determine the potential needforcorticosteroid, and(4)unmaskingofotherwiseunsuspectednon-adherence to corticosteroid therapy.
Nitric oxide (NO) is now recognized as a biological mediator inanimals and humans. NO is produced by the human lung and ispresent in the exhaled breath. It has been implicated in the path-ophysiology of lung diseases, including asthma. The measure-ment of exhaled NO has been standardized for clinical use.Numerous studies have provided evidence regarding the appli-cations of NO measurements in clinical practice, together withthe performance characteristics and the strengths and the weak-nesses of the test. Based on this evidence, this Clinical PracticeGuideline is designed to guide clinicians as to how exhaled NOmeasurements should be used and interpreted.
EVIDENCE QUALITY AND RECOMMENDATIONS
These recommendations may vary with respect to the particulartarget population. Where this is the case, this has been included
This article has an online supplement, which is available from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 184. pp 602–615, 2011DOI: 10.1164/rccm.912011STInternet address: www.atsjournals.org
in the recommendation. If not stated, then the recommendationapplies to patients with asthma.
d We recommend the use of FENO in the diagnosis of eosin-ophilic airway inflammation (strong recommendation,moderate quality of evidence).
d We recommend the use of FENO in determining the likeli-hood of steroid responsiveness in individuals with chronicrespiratory symptoms possibly due to airway inflammation(strong recommendation, low quality of evidence).
d We suggest that FENO may be used to support the diagnosisof asthma in situations in which objective evidence is needed(weak recommendation, moderate quality of evidence).
d We suggest the use of cut points rather than referencevalues when interpreting FENO levels (weak recommenda-tion, low quality of evidence).
d We recommend accounting for age as a factor affectingFENO in children younger than 12 years of age (strongrecommendation, high quality of evidence).
d We recommend that low FENO less than 25 ppb (, 20 ppbin children) be used to indicate that eosinophilic inflam-mation and responsiveness to corticosteroids are less likely(strong recommendation, moderate quality of evidence).
d We recommend that FENO greater than 50 ppb (. 35 ppbin children) be used to indicate that eosinophilic inflam-mation and, in symptomatic patients, responsiveness tocorticosteroids are likely (strong recommendation, moder-ate quality of evidence).
d We recommend that FENO values between 25 ppb and50 ppb (20–35 ppb in children) should be interpreted cau-tiously and with reference to the clinical context. (strongrecommendation, low quality of evidence).
d We recommend accounting for persistent and/or high aller-gen exposure as a factor associated with higher levels of FENO
(strong recommendation, moderate quality of evidence).
d We recommend the use of FENO in monitoring airway in-flammation in patients with asthma (strong recommenda-tion, low quality of evidence).
d We suggest using the following values to determine a sig-nificant increase in FENO: greater than 20% for values over50 ppb or more than 10 ppb for values lower than 50 ppbfrom one visit to the next (weak recommendation, lowquality of evidence).
d We suggest using a reduction of at least 20% in FENO forvalues over 50 ppb or more than 10 ppb for values lowerthan 50 ppb as the cut point to indicate a significant re-sponse to antiinflammatory therapy (weak recommenda-tion, low quality of evidence).
Conclusion: Advances in technology and standardizationhave made FENO measurement simple, permitting its use as abiomarker that adds a new dimension to the traditional clinicaltools in the assessment and management of airways diseases.These guidelines for interpretation of FENO measurements aremeant to enhance their clinical utility, but more work is still neededto better define the use of FENO in different clinical settings.
INTRODUCTION
NO has long been known as an atmospheric pollutant present invehicle exhaust emissions and cigarette smoke, and more re-cently its clinical importance as a biological mediator in animals
and humans has been recognized (1, 2). NO is present in virtu-ally all mammalian organ systems and is produced by the hu-man lung. It is present in the exhaled breath of all humans (3).NO is recognized to play key roles in virtually all aspects of lungbiology and has been implicated in the pathophysiology of lungdiseases, including asthma (4). The functions and effects of NOin the lung/airways reflect its key roles as a vasodilator, bron-chodilator, neurotransmitter, and inflammatory mediator (3).Patients with asthma have high levels of NO in their exhaledbreath and high levels of inducible nitric oxide synthase (NOS2)enzyme expression in the epithelial cells of their airways, sug-gesting a role for NO in asthma pathogenesis (5). NO is a highlyreactive molecule/free radical and may have oxidant propertiesdirectly or in the form of the more noxious peroxynitrite. Theseproperties give NO its bactericidal and cytotoxic effects andmay participate in host defense by mediating antimicrobial ac-tivity and cytotoxicity for tumor cells (4). The exact pathophys-iological role of NO in the airways and lungs is complex (4, 6–8).On the one hand, it may act as a proinflammatory mediatorpredisposing to the development of airway hyperresponsiveness(AHR) (4, 9). On the other, under physiological conditions NOacts as a weak mediator of smooth muscle relaxation, and pro-tects against AHR (4, 10). In exhaled air, NO appears to orig-inate in the airway epithelium (5, 11–15), as a result of NOS2up-regulation which occurs with inflammation (5, 12, 13, 16).Thus, exhaled NO may be regarded as an indirect marker forup-regulation of airway inflammation.
The field of exhaled NO measurement has developed remark-ably over the last 15 years.The use of chemiluminescence analyzersallowed for the detection of NO in exhaled breath in the early1990s (17). Patients with asthma were found to have high FENO
in their exhaled breath (18–20) that decreased in response totreatment with corticosteroids (21). This quickly prompted theevaluation of FENO as a potential noninvasive method to diagnoseasthma and monitor the response to antiinflammatory therapy.
Advantages for FENO include the noninvasive nature of the test,ease of repeat measurements, and the relatively easy use in patientswith severe airflow obstruction where other techniques are difficultto perform (22). By providing information about airway inflamma-tion (23, 24), FENO adds a new dimension to the traditional clinicaltools (history, physical exam, and lung function tests).
Before FENO could become useful as a clinical tool, severalissues needed to be addressed (25). In particular, the methodsand equipment for measuring FENO needed to be standardized(26, 27). Large population studies were needed to determineeffect of confounding factors and provide the normal range oruseful cutoff points of FENO levels (22, 25). Most of these issueshave either already been addressed or are currently under in-vestigation, allowing FENO measurement to make the transitionfrom research into the clinical arena. Last, but not least, inter-pretative strategies need to be devised and put in place for thedifferent potential uses and applications (28). The purpose ofthis document is to address this last requirement.
Wherever possible, the recommendations are based on pub-lished material, including abstracts, as referenced, but they aresupplemented by nonsystematic observations of experts in thefield. The guidelines are provided with the clear understandingthat this will be a rapidly evolving area and that periodic updat-ing will be required.
METHODS
Committee Composition, Meetings, and
Document Preparation
The project Chair (R.A.D.) assembled a group of internationalexperts in exhaled nitric oxide. Their expertise was in clinical
American Thoracic Society Documents 603
care, clinical research, or basic science in the area of asthma and/or nitric oxide (five pulmonologists [R.A.D., S.C.E., A.C.O.,A.L.P., D.R.T.], an allergist [P.B.B.], two physiologists [C.G.I.,J.O.L.], and one pediatric pulmonologist [M.W.L.]). The outlineof the Report was proposed by the Chair and modified and agreedupon following input from all Committee members. The Commit-tee was divided into subgroups, each was assigned a specific sec-tion, and preliminary drafts were developed. Three face-to-facemeetings and nine teleconferences were held. The outline andthe drafts were reviewed, and evidence-based recommendationswere discussed and finalized by consensus. Committee membersdisclosed all potential conflicts of interest. All disclosed conflicts ofinterests were reported to the Chair of the Ethics and Conflict ofInterest Committee of the ATS. These were reviewed in detail,and members with perceived conflicts abstained from the discus-sion of specific questions related to their conflicts of interest. Fur-thermore, members were reminded to consider their own andother members’ potential conflicts of interest during the meet-ings. The Chair (R.A.D.) integrated the draft sections and com-posed the entire document into a preliminary document that wascirculated among the committee members for further input. Therevised document incorporated the comments and input from allCommittee members.
Document Structure
This document is structured to provide an evidence-based reviewof the current state of knowledge regarding the application andinterpretation of FENO measurements in clinical practice. Therecommendations regarding interpretive strategy were orga-nized around specific questions according to the GRADE ap-proach to assessing the quality of the evidence (Summary TableE1 in Appendix in online supplement) (29, 30). Relevant sec-tion topics and questions were identified by the Committee.Committee members were asked to review the current evidenceby independently completing a pragmatic systematic review of theliterature using PubMed and OVID. Each Committee memberwas asked to assess the identified literature relevant to his/hersection, and decide about inclusion of individual articles. MED-LINE searches from 1993 to December 2008 were performed byCommittee members, with periodic updates during documentdevelopment and finalization. Searching the literature before1993 was not done systematically since the discovery of nitricoxide in asthma was first reported in 1993. The search wasaugmented by searches of Committee member files. The litera-ture search was limited to all relevant studies including random-ized controlled trials, cohort studies, case-control studies, andcross-sectional studies published in the English language. Sec-tions that did not yield specific recommendations were writtenafter a thorough review of the available literature in a narrativereview format.
Quality of Evidence and Strength of Recommendations
The quality of evidence was determined according to the ATSGRADE criteria (30). For each question, the Committeegraded the quality of the evidence available (high, moderate,low, or very low), and made a recommendation for or against.Recommendations were decided by consensus. Recommenda-tions were either “strong” or “weak.” The strength of a recommen-dation reflects the extent to which one can, across the range ofpatients for whom the recommendation is intended, be confidentthat desirable effects outweigh undesirable effects (30). Consensuson the recommendations was reached among all the members ofthe Committee. The strength of a recommendation has importantimplications for patients, clinicians, and policy makers (30).
Strong recommendation.
d Patients: Most people in this situation would want the recom-mended course of action and only a small proportion would not
d Clinicians: Most patients should receive the recommendedcourse of action
d Policy makers: The recommendation can be adopted as a policyin most situations
Weak recommendation.
d Patients: The majority of people in this situation would want therecommended course of action, but many would not
d Clinicians: Be more prepared to help patients to make a decisionthat is consistent with the patient’s own values
d Policy makers: There is a need for substantial debate and in-volvement of stakeholders
Why Should a FENO Test Be Obtained?
Common reasons for measuring FENO.
d To assist in assessing the etiology of respiratory symptoms
d To help identify the eosinophilic asthma phenotype
d To assess potential response or failure to respond to antiinflam-matory agents, notably inhaled corticosteroids (ICS)
d To establish a baseline FENO during clinical stability for subse-quent monitoring of chronic persistent asthma
d To guide changes in doses of antiinflammatory medications: step-down dosing, step-up dosing, or discontinuation of antiinflamma-tory medications
d To assist in the evaluation of adherence to antiinflammatorymedications
d To assess whether airway inflammation is contributing to poorasthma control particularly in the presence of other contributors(e.g., rhinosinusitis, anxiety, gastro-esophageal reflux, obesity, orcontinued allergen exposure).
Can FENO Be Used to Diagnose Asthma?
Asthma is a clinical diagnosis and there is no single diagnostictest for the disease. The background pathology of asthma is oftenbut not always due to eosinophilic airway inflammation. The twoare not synonymous. This is extremely important in the interpre-tation of FENO measurements. It is often claimed that FENO isa diagnostic test for asthma, but in cases of asthma not due toairway eosinophilia, FENO may be low. Similarly, the value ofexhaled FENO as a predictor of steroid responsiveness is higheven in the absence of induced sputum eosinophils (31).
- Recommendations:
We recommend the use of FENO in the diagnosis of eosinophilicairway inflammation (strong recommendation, moderatequality of evidence).
We recommend the use of FENO in determining the likelihoodof steroid responsiveness in individuals with chronic respira-tory symptoms possibly due to airway inflammation (strongrecommendation, low quality of evidence).
We suggest that FENO may be used to support the diagnosis ofasthma in situations in which objective evidence is needed(weak recommendation, moderate quality of evidence).
FENO is associated with eosinophilic airway inflammation. There areseveral inflammatory phenotypes in asthma most commonly de-scribed as eosinophilic, neutrophilic, mixed, and paucigranulo-cytic (32). Determination of the subtype may help a physician
604 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011
decide which therapies to select or stop (33–35). Given the long-established relationship between eosinophilic inflammation andsteroid responsiveness in airways disease, the finding that FENO
correlates with eosinophilic inflammation suggests its use as in-direct indicator not only of eosinophilic inflammation, but moreimportantly of the potential for steroid responsiveness (36–42).
There is little evidence directly demonstrating that eosino-philic airway inflammation increases FENO by increasingNOS2 expression or activity (43). However, eosinophilic airwayinflammation may affect FENO indirectly through NOS2 or viaother enzyme pathways. Numerous studies describe the rela-tionship between FENO and eosinophilic airway inflammation.Eosinophils can be measured in sputum, bronchoalveolar la-vage, and biopsies. There are also reports of correlation be-tween FENO and blood eosinophils (44–46). Warke andcoworkers reported that in bronchoalveolar lavage fluid thecorrelation between eosinophils and FENO was 0.78 (P ,0.001) (40). Payne and colleagues reported that the correlationbetween FENO and eosinophils in bronchial biopsies was 0.54(P ¼ 0.03) (47), but in contrast Lim and coworkers were unableto find a significant correlation in the biopsies (48). In inducedsputum, the correlation between FENO levels and eosinophilsranges from 0.35 (n ¼ 25, P ¼ 0.09) (36) to 0.48 (n ¼ 35, P ¼0.003) (49) to 0.62 (n¼ 78, P, 0.001) (50). In the largest study todate (n ¼ 566), the correlation was of a similar order (0.59, P ,0.001) (39). In this last study, FENO of 36 ppb (at a flow rate of50 ml/s) had a sensitivity and specificity for sputum eosinophiliaof more than 3% (the cut point deemed by the authors to beclinically significant) of 78% and 72%, respectively. In the studyby Shaw and colleagues, a FENO of less than 26 ppb had a negativepredictive value of 85% for sputum eosinophils less than 3% (51).Similarly, Porsbjerg and coworkers have reported that with FENO
less than 27ppb, it is unlikely that sputum eosinophils will begreater than 1% (52). Thus a low FENO is of value in determiningthe absence of eosinophilic, and, by inference, the likely absenceof steroid-responsive airway inflammation.
These limited correlations reflect the fact that whereas spu-tum eosinophilia is always abnormal, exhaled nitric oxide ispresent even in health with its distribution skewed to the right.It is also necessary to bear in mind that negative and positivepredictive values are limited in their generalizablity, given thatthey depend on the prevalence of the condition in the testedpopulation. Importantly, two studies have shown that the rela-tionship between FENO levels and airway eosinophilia is indepen-dent of the diagnosis of asthma as reported in patients withchronic obstructive pulmonary disease (COPD) (53), and witheosinophilic bronchitis (54). Furthermore, NO and NO metabo-lites in the airway (e.g., peroxynitrite) alter the REDOX balancein the airways, may cause inflammation, and are in some partsteroid sensitive. Thus NO production is to some extent indepen-dent of eosinophilic inflammation (4).
FENO predicts likelihood of corticosteroid responsiveness. Treatmentresponse in asthma is heterogeneous (55). Not all patients re-spond to corticosteroids and an important reason to use FENO isto help decide who might benefit from steroid treatment, andwho should try other medications (e.g., leukotriene modifiers).FENO may also be used to determine patients in whom steroidtherapy may be safely withdrawn. FENO has been shown to pre-dict the likelihood of steroid responsiveness more consistentlythan spirometry, bronchodilator response, peak flow variation,or AHR to methacholine (56–58). The optimum cut point in thestudy by Smith and coworkers (56), was 47 ppb, with a negativepredictive value of 89% for the change in FEV1 with inhaledsteroids. The predictive values were similar for alternative end-points. Even when patients do not demonstrate sputum eosin-ophilia, FENO is highly predictive of steroid response (at a cut
point of 33 ppb) (31). These data are consistent with studies inwhich high FENO (. 47 ppb) predicts the likelihood of loss ofcontrol when inhaled steroids are reduced or withdrawn in chil-dren with a confirmed diagnosis of asthma (59). Conversely, lowFENO (, 22 ppb) predicts the likelihood of successful reductionor withdrawal of inhaled steroids (positive predictive value,92%) (60). Again, these outcomes may differ somewhatdepending on the target population: for the most part these dataare derived from patients with mild to moderate asthma. Insummary, depending on the prevalence of eosinophilic airwayinflammation in the target population, FENO measurements mayprovide a signal that is helpful in identifying patients withasthma-like symptoms who are likely to benefit (or not) fromcorticosteroid treatment.
FENO can support a diagnosis of asthma. The diagnosis of asthmais well defined, and the background pathology is often but notalways due to eosinophilic airway inflammation. Early studiesin populations comprising mainly patients with eosinophilicasthma explored the performance characteristics of FENO asa diagnostic test. The predictive values for FENO (usually atcut points of . 25 ppb) were shown to be sufficiently robustfor it to be used in this context (23, 61, 62). Further, the pre-dictive values for FENO are higher than for conventional meas-urements such as peak flows and spirometry (23), and similar tothose associated with bronchial challenge tests (62). However,in general, in patients presenting with variable cough, wheeze,and shortness of breath, an increased FENO provides supportiverather than conclusive evidence for an asthma diagnosis. Asstated, the limitations to the diagnostic role of FENO arise prin-cipally because airway inflammation in asthma is heterogeneousand is not always associated with increased FENO (e.g., neutro-philic airway inflammation). Similarly, in patients who havealready been treated with inhaled steroids, the test may befalsely negative. Thus, the importance of FENO lies in its poten-tial to identify steroid responsiveness, rather than the exactclinical diagnosis. This information is much more clinically rel-evant because it enables the clinician to bypass an empiric “trialof steroids” or unnecessary long-term corticosteroid treatment.
FENO may predict AHR. Irrespective of the specific underlyinginflammatory signal which FENO represents, measurements ap-pear to reflect the dynamic interrelationships between the re-sponse to allergen or other triggers and evolving eosinophilicairway inflammation/AHR (4, 7, 8, 63). Serial FENO levels in-crease progressively in response to allergen exposure and theadvent of airway symptoms (63). Because of the practical diffi-culties involved in measuring AHR, especially in children, it wasinitially thought that FENO might be used as a surrogate markerfor AHR. The relationship between NOmetabolism and AHR inasthma is complex (64). When FENO was used to predict the pres-ence of AHR, the studies reveal inconsistent relationships andcorrelations are generally low. The clinical interpretation of FENO
in relation to AHR is even more problematic in subjects who aretaking ICS (9, 65) and with long-standing as opposed to recentlydeveloped asthma (66). This is demonstrated in studies designedto evaluate pathophysiological relationships in clinical asthmausing factor analysis: AHR, airway inflammation, and FENO be-long to different domains (66–68). However, in one study FENO
has been used as a surrogate for AHR testing to support the di-agnosis of asthma in children, and the data appear to support itsuse in this limited context (62).
Is There a Normal FENO Value?
This section will discuss the normal ranges of FENO. We will alsodiscuss the important clinical cut points and the rationale forselecting these cut points to be used in the interpretation of an
American Thoracic Society Documents 605
elevated or reduced FENO value. It is important to choose theappropriate cut point in relation to the clinical setting and ques-tion. While this section and the accompanying tables (see Tables3–5) focus on asthma and airway diseases/inflammation, othercauses of high and low FENO levels are listed in the Appendix inthe online supplement.
- Recommendations:
We suggest the use of cut points rather than reference valueswhen interpreting FENO levels (weak recommendation, lowquality of evidence).
We recommend accounting for age as a factor affecting FENO inchildren younger than 12 years of age (strong recommenda-tion, high quality of evidence).
Normal Values versus Relevant Cut Points for FENO
This section will discuss the normal ranges of FENO and what arethe important clinical cut points to be used in the interpretationof an elevated or reduced FENO value. It is unlikely that refer-ence values derived from a “normal” population will be ashelpful as cut points in patients with airways disease or re-spiratory symptoms. The distribution of FENO in an unselectedpopulation is skewed to the right (see Figure 1). Even whenindividuals with atopy or diagnosed asthma are excluded, theupper limit of “normal” ranges from 27 to 57 ppb dependingon sex (69). This overlaps with the range of values obtained in
populations with asthma in relation to sputum eosinophilia (seeFigure 1). In a clinical study, Shaw and colleagues reported thatthe optimum cut point for a clinically significant FENO (corre-sponding to a sputum eosinophil count of > 2%) was 26 ppb(51). Similarly, studies designed to determine the optimum cutpoint to diagnose asthma using FENO have usually pointed toa diagnostic cut point ranging from 20 to 25 ppb (23, 70–72).However, in patients with stable, well-controlled asthma, FENO
values range from 22 to 44 ppb (73). Clearly, there is consider-able overlap between mean FENO levels in healthy and popula-tions with stable asthma. This is illustrated in Figure 2.
Confounding factors that may affect FENO. As discussed in the Ap-pendix in the online supplement, FENO values can be affected byseveral factors, including measurement technique, exhalationflow rate, nasal NO contamination, the NO analyzer used (74),age, height, smoking, and antiinflammatory medications. A num-ber of recent publications have reported reference values forFENO in adults (69, 75–79) (Table 1) and children (76, 80–83).There are important differences between these studies withregard to the size of the examined population, as well as therange of statistical variables that have been included or excluded,limiting their value (76, 77, 80–83). Factors affecting populationFENO levels may be due to one or more variables including ge-netics, age, sex, atopy, weight and height, current smoking, anddiet. The importance of current smoking and atopic status isgenerally agreed upon (28), but there are inconsistencies betweenthe studies regarding which other factors ought to be accountedfor when deriving and applying reference values (Table 1). Moredetailed information on these biological sources of variability isprovided in the Appendix in the online supplement.
Age seems to be important in children (81), but there is lessagreement across the studies regarding age in adults, sex, andheight. In the largest study to date, Olin and coworkers identi-fied the importance of age and height as factors affecting FENO,but did not find any differences between males and females(69). In contrast, Travers and colleagues (78) and Taylor andcoworkers (84) reported consistently higher levels in males. Themagnitude of the effect of the patient-related factors alone or incombination is potentially clinically significant. This is demon-strated in Table 2 (data from Reference 69).
Thus, in our present state of knowledge the problems of mul-tiple confounding factors and overlap between normal popula-tions and populations with asthma preclude the routine applicationof reference values in the clinical setting. The Committee feltthat it is more relevant to identify clinically meaningful cut pointsrather than reference values to interpret FENO levels as outlinedbelow, keeping in mind that very few of these cut points are wellvalidated. At any one time, however, the most important con-sideration is whether or not the patient has current respiratorysymptoms or a prior diagnosis of airways disease; that is, the
Figure 1. Schematic representation of the distribution of FENO levels in
an unselected population of 2,200 male and female subjects. The me-
dian value was 16.0 ppb with a range of 2.4 to 199 ppb. The cut pointof 26 ppb is the optimum cut point for significant sputum eosinophilia,
indicating that up to 20% of individuals with an FENO greater than 25
ppb may not necessarily have sputum eosinophilia, and that the clinicalcontext requires to be taken into account. The data used to prepare this
composite figure were obtained from Shaw and colleagues (51) and
Olin and colleagues (73) after consultation with the authors.
Figure 2. An amplification of Figure 1 in which
the distribution of FENO in stable asthma is de-
picted as a dotted line. Taken from Olin andcolleagues (73). In that study, the 95% confi-
dence intervals for FENO in stable asthma was
reported to be 22 to 44 ppb. The cut point of
47 ppb is the optimum cut point for steroid re-sponsiveness in patients with nonspecific respi-
ratory symptoms. The other data used to
prepare this composite figure were obtained
from Smith and colleagues (56) after consulta-tion with the authors.
606 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011
interpretation of FENO levels should be determined in individualpatients with reference to the context in which the measurementis being obtained.
What Are the Clinically Significant Cut Points for FENO?
It is important to choose the appropriate cut point in relation tothe clinical setting and question. In this section, we discuss therationale for selecting these cut points (see Tables 3–5). Whilethis section and the accompanying tables focus on asthma andairway diseases/inflammation, other causes of high and lowFENO levels are listed in the Appendix in the online supplement.
- Recommendations:
We recommend that low FENO (, 25 ppb [, 20 ppb in chil-dren]) be used to indicate that eosinophilic inflammation and
responsiveness to corticosteroids are less likely (strong rec-ommendation, moderate quality of evidence).
We recommend that FENO . 50ppb (. 35 ppb in children)be used to indicate that eosinophilic inflammation and, insymptomatic patients, responsiveness to corticosteroids arelikely (strong recommendation, moderate quality of evidence).
We recommend that FENO values between 25 ppb and 50 ppb(20–35 ppb in children) should be interpreted cautiously withreference to the clinical context (strong recommendation,low quality of evidence).
Low FENO (, 25 ppb in adults; 20 ppb in children). In a symptomaticadult patient with a FENO of less than 25 ppb (20 ppb in chil-dren), eosinophilic airway inflammation is unlikely. This cutpoint is based on evidence from a number of sources includingthe study by Shaw and colleagues (51) and Porsbjerg and cow-orkers (52), studies investigating the role of FENO measure-ments to diagnose asthma (23, 70–72), and studies designed tooptimize ICS use (56, 60). The differential diagnosis for symp-tomatic patients with a low FENO is given in Table 3. In patientspresenting with nonspecific respiratory symptoms, low FENO
suggests alternative diagnoses which are not amenable to anincrease in inhaled or oral steroid therapy.
High FENO (. 50 ppb in adults, 35 ppb in children). High FENO islikely to indicate significant airway eosinophilia. It is also likelyto indicate that a symptomatic patient has steroid-responsiveairways inflammation (56, 57, 85, 86). The clinically significantcut point of 50 ppb is based on the results of pragmatic studies.However, this is a general guide and may vary slightly in in-dividual patients. Symptomatic steroid-naıve patients with highFENO are more likely to exhibit responsiveness to inhaled ste-roid therapy, irrespective of the diagnostic label (e.g., asthma ornonasthma), with an optimum cut point of 47 ppb (56). Inasymptomatic patients with stable asthma, the likelihood of re-lapse following withdrawal of ICS therapy is greatest in patientswhose FENO increases to above 49 ppb during the 4 weeks after
TABLE 1. STUDIES OF ONLINE FRACTION OF EXHALED NITRIC OXIDE VALUES AT EXHALATION FLOW RATE OF50 ml/s IN HEALTHY SUBJECTS
Author and Reference N Groups for which Reference Values Are Given “Normal Values” (ppb) Analyzer
Kharitonov 2003 (75) 59 Mixed population of adults and children Mean 16.3 ppb, ULN 33. NIOX (Aerocrine AB, Stockholm, Sweden)
Buchvald 2005 (76) 405 Children aged 4–17 yr Mean 9.7 ppb, NIOX (Aerocrine AB, Stockholm, Sweden)
Data also available by age stratification Upper 95% CI: 25.2
TABLE 2. FRACTION OF EXHALED NITRIC OXIDE 95% UPPERLIMITS, STRATIFIED FOR SEX AND ATOPY, ACCORDING TOHEIGHT AND AGE AMONG 1,131 HEALTHY LIFELONG NEVER-SMOKING SUBJECTS
HeightAge 25–49 yr Age 50–75 yr
(cm) Women Men Women Men
Subjects without Atopy (n ¼ 845)
150–159 25 27 34 32
160–169 26 30 36 35
170–179 28 33 39 39
180–189 30 37 41 44
190–199 — 42 — 49
Subjects with Atopy (n ¼ 286)
150–159 30 58 37 65
160–169 36 63 45 63
170–179 43 54 53 62
180–189 51 50 64 57
190–199 — 50 — 56
Data taken from Reference 69.
American Thoracic Society Documents 607
steroid withdrawal (59). The differential diagnosis for high FENO
is shown in Table 4.Intermediate FENO (between 25 ppb and 50 ppb in adults; 20–35 ppb in
children). The above data indicate that for FENO values between25 and 50 ppb, cautious interpretation is required. The weightplaced on an FENO result within this range will depend onwhether the test is being used diagnostically in a symptomaticsteroid-naıve subject, or whether the patient’s FENO has in-creased or decreased from a previous value by what is deemedto be a clinically significant amount in a patient who is beingmonitored over time.
- Recommendation
We recommend accounting for persistent and/or high allergenexposure as a factor associated with higher levels of FENO
(strong recommendation, moderate quality of evidence).
Persistently high FENO (. 50 ppb in adults, 35 ppb in children). In apatient with ongoing asthma, symptoms may occur despiteapparently adequate antiinflammatory treatment (87). In thecollective experience of the Committee, a common cause ofpersistently high FENO is poor adherence to ICS therapy. Otherexplanations could be poor inhaled drug delivery or continuedexposure to allergen (7, 8).
Continuing or increasing exposure to aeroallergens to whicha patient is sensitized may result in a rise in FENO, or the
persistence of an elevated FENO. The magnitude of the effectmay be sufficient for FENO levels to increase beyond the cutpoint of 50 ppb, and in some patients may occur even in theabsence of respiratory symptoms (88–91). More recent evidencesuggests that persistent high FENO in corticosteroid-treated indi-viduals with asthma may also reflect a highly reactive asthmaphenotype, and such patients need to be managed with caution(35). However, if the patient is asymptomatic and has a highFENO, then no change in treatment is required. There is a smallgroup of patients whose FENO remains high despite good asthmacontrol. This probably results from the fact that more than onefactor (i.e., not just eosinophilic airway inflammation) is responsi-ble for the elevated FENO. Another explanation may be that thehigh exhaled NO is derived from constitutive NOS sources whichare steroid insensitive. Thus, levels greater than 50 ppb in a well-treated asymptomatic patient may be “normal” for that specificpatient.
Can FENO Be Used to Monitor Airway Inflammation?
The change in FENO value following corticosteroid interventionmay be more valid than the absolute FENO value. The definitionof a clinically significant change in FENO, however, remains tobe established.
- Recommendations
We recommend the use of FENO in monitoring airway inflam-mation in patients with asthma (strong recommendation, lowquality of evidence).
TABLE 3. LOW FENO (, 25 ppb [, 20 ppb IN CHILDREN]): IMPLIESNONEOSINOPHILIC OR NO AIRWAY INFLAMMATION*
Diagnosis
In a symptomatic patient (chronic cough and/or wheeze and/or shortness
of breath for. 6 wk) presenting for the first time, the patient is unlikely to
benefit from a trial of inhaled corticosteroid treatment, possible etiologies:
No change in inhaled corticosteroid dosing, but refer to FENO trend
over time in individual patient
Withdrawing inhaled corticosteroid is likely to be followed by relapse
An increase in therapy is indicated as some patients are asymptomatic,
but the high FENO could be a risk factor for an upcoming exacerbation.
“High” FENO may be normal in a certain percent of the population
(Figure 1).
Definition of abbreviation: FENO ¼ fraction of exhaled nitric oxide.
*The interpretation of FENO is an adjunct measure to history, physical exam,
and lung function assessment.
For intermediate FENO (levels in the range 25–50 ppb [20–35 ppb in children]),
refer to Table 5.
608 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011
We suggest using the following values to determine a significantincrease in FENO: greater than 20% for values over 50 ppb ormore than 10 ppb for values lower than 50 ppb from one visitto the next (weak recommendation, low quality of evidence).
We suggest using a reduction of at least 20% in FENO for valuesover 50 ppb or more than 10 ppb for values lower than 50 ppb asthe cut point to indicate a significant response to antiinflamma-tory therapy (weak recommendation, low quality of evidence).
Monitoring Airway Inflammation in Asthma
Serial measurements obtained when patients’ asthma is bothstable and unstable allows each patient to act as his/her owncontrol when assessing subsequent measurements and as a result“personal best” can be used (92). The same cut points used indetecting airway inflammation apply when monitoring patientswith asthma. In asymptomatic individuals, including patientswith well-controlled asthma, low FENO suggests that ICS dosecould be reduced or even that ICS treatment may be withdrawnaltogether. In a study of children with stable asthma, withdrawalof ICS did not result in symptom relapse when FENO remainedconsistently low (optimum cut point 22 ppb) when measured2 to 4 weeks after treatment withdrawal (60). In symptomaticpatients with low FENO, strategies other than increasing the ICSdose should be pursued. Thus, FENO values which are eitherhigh or low are informative as to the etiology of current symp-toms particularly in patients with difficult asthma. Sequentialmeasurements may be important in determining trends. Therelatively rapid change in FENO in response to ICS is thoughtto add to its utility in monitoring adherence to and response tosuch therapy (93). However, as a predictor of asthma control,FENO is no better than more conventional lung function tests(51, 87, 94, 95). The predictive values of a single measurementof FENO for loss of asthma control are insufficiently sensitive orspecific to justify its use for this specific purpose (51, 94, 95).
Minimally Important Differences, and Prognostic Significance
of FENO
The within-subject coefficient of variation for FENO in healthysubjects is approximately 10%, or up to 4 ppb (75, 96). Thevariation increases to approximately 20% in patients with asthma(75, 96, 97). Since a change of 20% could be due to the variationin the FENO measurement, the Committee recommends a change
of at least 20% to indicate a significant rise or fall in FENO overtime or following an intervention. However, there are very fewdata that clarify what constitutes a clinically important change inindividual patients. In one study, FENO levels were 50% higherduring acute asthma compared with when stability was restored(98). Data obtained from steroid withdrawal studies show thatthe mean increase in FENO associated with the advent of loss ofcontrol ranges from 16 ppb (99) to 25 ppb (50), the latter repre-senting a 60% increase from baseline. However, the range of theincrease in FENO between stability and loss of control is high (upto 141 ppb) (50). More recently, Michils and colleagues havereported that the transition from good control to poorly controlledasthma is likely to be associated with a rise in FENO of 40% orgreater (100). An acute rise (over 12–24 h) in FENO may occurafter infection or exposure to an allergen to which the patient issensitized. The magnitude of the rise may be as high as 150 ppb.Ideally, one would wish that a minimally important change inFENO to a level that is above or below a particular cut point wouldprovide justification for a specific interpretation. Unfortunately,there are insufficient data to recommend this approach. Rather,the current FENO level, the direction and magnitude of any recentchange, and where the measured level sits in relation to the cutpoints for “high” or “low” values need to be taken into account.
Randomized trials designed to assess whether asthma out-comes are improved using regular FENO measurements as thebasis for adjusting the dose of ICS therapy have failed to showimportant benefits (51, 87, 95, 101, 102), although in one studyICS dose reduction was facilitated without compromisingasthma control (103). Thus in general, FENO measurements can-not be recommended for this purpose. A recent systematic as-sessment of published randomized trials of asthma therapyguided by FENO concluded that the mixed results of these stud-ies (the ASTRAL studies, an acronym for ASthma randomizedTReatment ALgorighm studies) were due to specific design andmethodological issues that may have led to incorrect conclu-sions (104). In his summary, Gibson highlights the followingproblems: (1) the dose–response relationship of the drugs usedin relation to the outcomes measured; (2) the effects of adher-ence and nonadherence; (3) the algorithms used and theiragreement with clinical decision making; (4) the selection ofFENO cut points/decision points. Gibson states that future studieswould require the use of an additional metric to assess the likeli-hood that any two algorithms (conventional and biomarker-guided) will give different ICS dosing decisions (104). In a more
TABLE 5. GENERAL OUTLINE FOR FENO INTERPRETATION: SYMPTOMS REFER TO COUGH AND/OR WHEEZE AND/ORSHORTNESS OF BREATH*
FENO , 25ppb FENO 25–50 ppb FENO . 50 ppb
(,20 ppb in children) (20–35 ppb in children) (.35 ppb in children)
Diagnosis
Symptoms present during
past 61 wk
Eosinophilic airway
inflammation unlikely
Be cautious
Evaluate clinical context
Eosinophilic airway inflammation
present
Alternative diagnoses Monitor change in FENO over time Likely to benefit from ICS
Unlikely to benefit from ICS
Monitoring (in Patients with Diagnosed Asthma)
Symptoms present Possible alternative diagnoses Persistent allergen exposure Persistent allergen exposure
Unlikely to benefit from increase
in ICS
Inadequate ICS dose
Poor adherence
Poor adherence or inhaler technique
Inadequate ICS dose
Steroid resistance Risk for exacerbation
Steroid resistance
Symptoms absent Adequate ICS dose
Good adherence
ICS taper
Adequate ICS dosing
Good adherence
Monitor change in FENO
ICS withdrawal or dose reduction may
result in relapse
Poor adherence or inhaler technique
Definition of abbreviations: FENO ¼ fraction of exhaled nitric oxide; ICS ¼ inhaled corticosteroid.
* The interpretation of FENO is an adjunct measure to history, physical exam, and lung function assessment. See text and Tables 3 and 4 for other details.
American Thoracic Society Documents 609
recent study, investigators aimed to evaluate the accuracy ofbaseline FENO to recognize individuals with difficult-to-treatasthma who have the potential to achieve control with a guide-line-based stepwise strategy (105). One hundred two consecutivepatients with suboptimal asthma control underwent stepwise in-crease in the treatment with maximal inhaled corticosteroids for1 month. Then, those who remained uncontrolled received oralcorticosteroids for an additional month. With this approach, 53patients (52%) gained control. A FENO cut point greater than orequal to 30 ppb demonstrated a sensitivity of 88% and a specific-ity of 91% for the identification of responsive individuals withasthma, and a value less than or equal to 30ppb had a negativepredictive value for steroid response of 92% (105). Thus, incor-porating optimal design features into future FENO studies shouldhelp in obtaining a better estimate of the value of FENO-guidedasthma therapy (104). Otherwise, a study is unlikely to detecta positive result in favor of one decision-making algorithm versusthe other, even if one truly exists.
How Should a FENO Measurement Be Interpreted
and Reported?
1. Assure proper methodology: follow ATS/ERS guidelines. ATS/ERSguidelines for the measurement of FENO have been publishedand are the current standard (26, 27). These guidelines should befollowed carefully to obtain accurate and reproducible measure-ments. These guidelines should be used in conjunction with FDA-approved instructions for the use of specific nitric oxide analyzers.As additional instruments using different technologies to measureFENO become available, these guidelines as well as the scope ofFDA endorsements are likely to change.
2. Determine the reason for the test and the type of subject being tested:does the patient have asthma-like symptoms OR an already establisheddiagnosis of asthma? The interpretation of FENO begins withwhether a patient’s symptoms are nonspecific and as yet undi-agnosed, or whether they have a confirmed diagnosis of asthma.This upfront distinction between the diagnostic and monitoringuses of FENO allows for a more appropriate interpretation of theresults as outlined in Table 5. Other factors to take into accountinclude whether the subject is a smoker or is on antiinflamma-tory medications, as well as his/her height and age.
3. Interpretation of FENO measurement: clinically relevant cut points.
The purpose of measuring FENO is to determine whether thevalue is within normal limits, high, or low. In addition, whenmonitoring over time, one must be able to determine whena significant change (increase) has taken place. After correctmeasurement, and with reference to factors which may be af-fecting the measurement (e.g., current smoking). Interpretationcan be made as follows (see also Table 5):
d , 25ppb (, 20ppb in children): eosinophilic inflammation andresponsiveness to ICS (post-bronchodilator FEV1) are unlikely.
d . 50ppb (. 35ppb in children): eosinophilic inflammation islikely; responsiveness to ICS (post-bronchodilator FEV1) islikely.
d Values between 25ppb and 50ppb (20–35ppb in children) must beinterpreted cautiously with reference to the clinical context.
d An increase of . 20% and more than 25ppb (20ppb in children)may be significant but there are wide inter-individual differences.
d A minimally important decrease of the FENO value is defined asa difference larger than 20% for values over 50ppb or more than10ppb for values lower than 50ppb from one visit to the next.A reduction of an elevated FENO of more than 20% thatoften occurs 2–6 wk after initiation of anti-inflammatory therapysupports that the treatment was successful in reduction ofinflammation.
4. Minimum reporting requirements for FENO. When reportingFENO results, a minimum information set should be included.This should include but not be limited to: date, time of the day,age, sex, ethnicity, height, smoking status, reason for the test,and prior diagnosis (if known), and whether or not the patientwas using inhaled or oral corticosteroids at the time of testing.The format of the reporting should include the device used tomake the measurement, the number of measurements made,and the flow rate (currently approved FDA devices use 50 ml/s flow rate). One can choose to include all measurements per-formed or just the mean value. Results of previous testing (ifavailable) should be included. A listing of the relevant cut pointvalues is usually helpful.
Other Situations in which FENO May Be Useful
These are emerging areas for the use of FENO in the clinicalsetting, but there is not enough literature to provide specificguidelines for their application (106).
COPD. The exact role of exhaled nitric oxide measurementsin patients with establishedCOPD remains to be defined. In a sig-nificant number of patients, an overlap syndrome comprising fea-tures of both asthma and COPD is found (53). The airwayinflammatory cell infiltrate may be mixed, including eosino-philic inflammation. Studies show that, at least in the short term,the response to corticosteroids is likely to be greater in patientswith COPD who also have sputum eosinophilia (107, 108) orelevated FENO (109). This raises the possibility that FENO meas-urements might be used in predicting steroid responsiveness inCOPD. In a small group of 19 patients, Zietkowski and cow-orkers reported a significant correlation between baseline FENO
and DFEV1 after 2 months with inhaled budesonide 800mg/day(108). de Laurentiis and colleagues (110) reported greater FENO
variability in patients with COPD who subsequently developexacerbations. More recently baseline FENO was found to bea predictor for changes in airflow obstruction, but not im-provements in functional exercise capacity or health-relatedquality of life, with corticosteroid therapy (56). There is alsosome early evidence that a raised FENO predicts FEV1 responseto ICS in COPD (111, 112).
Pulmonary hypertension. NO is one of the important pathophys-iological mediators of pulmonary hypertension (113, 114). It isimportant to point out, however, that while NO is the mostrecognized product of NOS, it is not the only one and an activitythat is inhibited by NOS inhibition is not necessarily caused byNO (115–119). In the case of pulmonary hypertension for ex-ample, NO concentrations 1,000 times higher than those pro-duced by NOS endogenously (normally present in the airways)are required for therapy, and pulmonary hypertension can betreated by nitrogen oxides such as ethyl nitrite that do not pro-duce any nitric oxide at all (119). Thus in this sphere, we use NOto refer to NOS activity, recognizing that NO is a biomarker forNOS activity without always being the effector molecule. Inaddition to vasodilatation, NO regulates endothelial cell pro-liferation and angiogenesis, and maintains overall vascularhealth (121, 122). Interestingly, patients with pulmonary hyper-tension have low levels of FENO (123). Although this is a farmore complex issue than the simple lack of a vasodilator (124),giving NO therapeutically seems to work well (125). Therapiesthat target the NO pathway have revolutionized the treatmentof this disease, including the widely used phosphodiesterasetype 5 (PDE5) inhibitors, which prevent the breakdown of theNO effector molecule 39,59-cyclic guanosine monophosphase(cGMP), thus prolonging NO effects on tissues (122). The NOdeficiency state in patients with pulmonary hypertension alsoimproves with other therapies that do not directly target the
610 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 184 2011
NO pathway like prostacyclins and endothelin receptor antag-onists (125, 126). This seems also to have a prognostic signif-icance, with improved survival in patients who respond totherapy with higher FENO levels compared with those whodo not change their FENO levels in response to therapy(127). The low FENO levels in patients with pulmonary hyper-tension and the improvement with effective therapies suggestthat monitoring NO levels over time may be a useful nonin-vasive marker to evaluate response to or failure of medicaltherapy in these patients (127).
Cystic fibrosis and nasal NO measurements. Continuous and highproduction of NO takes place in the human nose and paranasalsinuses (128, 129), and this NO is readily measurable by non-invasive techniques (130). It has been shown that the nasal NOlevels are altered in several respiratory disorders—includingprimary ciliary dyskinesia (PCD) (129), cystic fibrosis (CF)(131, 132), and allergic rhinitis (133, 134), and this has led tothe proposal that nasal NO may be clinically useful in diagnosisand monitoring of these diseases. The levels of nasal NO areuniformly extremely low in patients with PCD, and the sensi-tivity and specificity of the test in this setting is excellent (135–139). The low levels of NO in CF are related to the absence ofNOS2 expression in the airway epithelium, which supports theconcept of NOS2 contribution to much of the NO detectable inexhaled breath (140–142). There is now abundant evidencethat NO levels in CF are affected by a variety of other pathwaysas well. In addition to NOS2, determinants of exhaled NO inCF include arginase activity (143), superoxide levels (144),S-nitrosothiol metabolism (145), and denitrification pathways/prokaryotic nitrogen oxide metabolism (146, 147). Thus, thesevarious determinants are all important when it comes to clinicalinterpretation FENO in CF. As such, response to arginine, re-sponse to antioxidants, response to inhaled nitrosothiols, andresponse to antimicrobial therapy might potentially be monitoredin CF, to some extent, by monitoring FENO. Although FENO islow in PCD, the diagnostic accuracy is considerably greater fora nasal NO test. Therefore this test is attractive for screening forPCD, prior to confirmatory testing (e.g., biopsies with analysis ofciliary structure). In contrast to FENO, a single standardized pro-cedure has not yet been defined for measuring nasal NO. Untilthis has been agreed upon, nasal NO levels are not yet recom-mended in routine clinical practice.
In summary, the use of FENO in COPD and pulmonary hy-pertension and the use of nasal NO in diagnosis and monitoringof other respiratory disorders (e.g., allergic rhinitis, sinusitis,nasal polyposis, CF) are potentially of interest, but more re-search is needed before we know how clinically useful thesetests can be for these disorders.
Conclusions and Future Directions
Advances in technology and standardization have made FENO
measurements simple, permitting their use as a biomarker in theassessment of inflammatory airways diseases. It is widely ac-knowledged that asthma is a heterogeneous disease with a vari-ety of underlying pathophysiological abnormalities. FENO playsa role in identifying these different phenotypes (4, 7, 8, 34, 35,148). Measurements are easily performed in different settingsand may be used in diagnosis and monitoring. Large populationstudies have identified various confounders that affect FENO
including age, sex, and height, among others. Consistent obser-vations indicate that atopic individuals have higher FENO levelswhile smokers tend to have lower FENO levels (69, 76–78). Ref-erence values have been derived from large population studies,but in practice they have limited application. Rather, evidence-based cut points that are shown to have diagnostic significance
appear to be more relevant. When monitoring individual patientswith asthma and assessing their treatment requirements, achiev-ing “personal best” rather than “normal” values is more helpful.In many patients, changes in FENO in relation to a baseline whenclinically stable may be even more relevant. FENO values ofthemselves do not justify a diagnosis or change in treatment.Rather, they need to be interpreted in relation to the clinicalcontext as discussed in this Guideline. They may be particularlyuseful in understanding patients with asthma in whom morethan one factor is contributing to respiratory symptoms (e.g.,obesity, anxiety) and for whom clinical decision making isdifficult. Another potential use of FENO might be during in-halation challenge testing. That is, as with spirometry, givingan allergen inhalation challenge while measuring changes inFENO before and after the challenge. This may be potentiallyuseful in the assessment of occupational asthma (149, 150).
Although these guidelines for interpretation of FENO meas-urements will enhance their clinical utility, we need to continueto investigate how to interpret FENO measurements in differentclinical settings. Inclusion of FENO as an endpoint in clinicaltrials would be very helpful in understanding the role of FENO
in monitoring response to therapy (151). Furthermore, FENO
measurement in large population-based studies like the Na-tional Health and Nutrition Examination Survey (NHANES)would provide more information on normative values (152). Thus,the guidelines provided here will need to be periodically updatedwith regard to new developments in this rapidly evolving field.
This official Clinical Practice Guideline was prepared by an ad hoccommittee of the Assembly on Allergy, Immunology and Inflam-mation (AII).
Members of the Committee:RAED A. DWEIK (Chair), M.D.PETER B. BOGGS, M.D.SERPIL C. ERZURUM, M.D.CHARLES G. IRVIN, M.D.MARGARET W. LEIGH, M.D.JON O. LUNDBERG, PH.D.ANNA-CARIN OLIN, PH.D.ALAN L. PLUMMER, M.D.D. ROBIN TAYLOR, M.D., D.Sc.
Author Disclosure: R.A.D., M.W.L., and A.L.P. reported that they received nopayments or services from a third party for the work submitted, and had norelevant financial activities outside the submitted work. C.G.I. reported consul-tancies with Critical Therapeutics and Sepracor, and advisory committee servicefor Genentech. He also received lecture fees from Merck, research support fromGlaxo Smith Kline and Sepracor, and royalties from book publishers. P.B.B. hasreceived consultancy fees, lecture fees, and fees for clinical research fromAerocrine and Apieron, manufacturers of FENO measuring equipment. S.C.E.reported research support from Asthmatx. J.O.L. reported ownership of sharesin Aerocrine AB, which manufactures a system for measuring exhaled nitric oxide.He also reported conference support from Hope Pharmaceuticals and Ikaria.A-C.O. reported research support from Astra Zeneca Sweden and lecture feesfrom Aerocrine AB. D.R.T. reported research support from Aerocrine AB.
References
1. Ignarro LJ, Buga GM,Wood KS, Byrns RE, Chaudhuri G. Endothelium-
derived relaxing factor produced and released from artery and vein is
nitric oxide. Proc Natl Acad Sci USA 1987;84:9265–9269.